Human immunodeficiency virus, HIV, is the etiological agent of AIDS. The viral promoter elements located in the long terminal repeats (LTRs) are the target of the transactivator, Tat. The core domain of Tat is phylogenetically the most conserved part of the protein and is thought to contribute to the binding of Tat to the TAR element. Here the applicants propose the study of specific core inhibitors from the Tat protein. Preliminary data presented here indicate that: i) The core peptide derivatives are specific to Tat transactivation and bind to kinase(s), which phosphorylate relevant substrates involved in HIV-1 transcription. They now have evidence that the kinase involved in HIV transcription affected by the peptide inhibitor is DNA-PK, and at least one of the relevant substrates for HIV transcription and DNA-PK phosphorylation is transcription factor Sp1. ii) In the absence of Tat crystal structure, NMR data indicates a loop of 10 amino acids in the core inhibitory domain, which may serve as a "true" lead compound for peptidomimetic or pharmacophor studies.iii) The core peptide derivatives inhibit syncytia (SI) and none-syncytia inducing (NSI) HIV-1 viruses in T-lymphocytic, monocytic and pro-myelocytic cells. Studies are proposed to determine target(s), range and specificity of the core peptides in cell lines and PBMCs.